Microfluidics is the science and technology of systems that process or manipulate small (10−9 to 10−8 L) amounts of fluids, using channels with dimensions of tens to hundreds of micrometers (see G. M. Whitesides. Nature 442, 368 (2006)). Over the last decade, a broad range of applications of microfluidics has been developed that included bioanalyses, syntheses of organic, inorganic, and bioorganic compounds, and the screening of conditions for protein crystallization.
Recently, microfluidic syntheses of polymer particles with controllable dimensions, shapes, and structures have attracted significant industrial interest. Potential applications of the microreaction technology include the production of ion exchange resins, calibration standards, spacers for electrochromic windows, microbeads for chromatography and biomedical purposes, and for the encapsulation of liquid ingredients. Currently, the productivity of a single microfluidic reactor is on the order of grams/hour. It is unlikely that without a significant increase in the productivity of microfluidic reactors this technology will ever find major industrial applications.
Recently, microfluidic emulsification allowed for the generation of droplets with precisely controlled compositions, morphologies, and volumes. Synthesis performed in these droplets has attracted great interest in materials and polymer science, and proved useful in the chemical, pharmaceutical, food, nutrition, and cosmetics fields. Miniaturization of continuous chemical reactions by compartmentalizing them in droplets provided efficient heat and mass transfer, precise control of the timing of reactions, and the ability to synthesize and transport gaseous, liquid and solid reagents and products (see H. Song; D. L. Chen; R. F. Ismagilov. Angew. Chem., Int. Ed. 45, 7336 (2006)). The use of these droplets as microreactors has generated a rapidly growing field of research and led to a number of new technology platforms (see H. Song; D. L. Chen; R. F. Ismagilov. Angew. Chem., Int. Ed. 45, 7336 (2006); M. Seo; S. Xu; Z. Nie; P. C. Lewis; R. Graham; M. Mok; E. Kumacheva. Langmuir 21, 4773 (2005); and A. Gunther, K F. Jensen. Lab Chip 6, 1487 (2006)).
Presently, applications of droplets produced by means of microfluidics can be tentatively categorized in two groups, namely, “discovery” and “development.” The first group of applications aims at studies of fast reactions and processes in e.g., drug discovery, gene expression analysis, bioassays, and the optimization of formulations for chemical synthesis. These applications generally require reactions to be performed on a microscale, since reagents are generally expensive or are only available in limited amounts. The second group of applications embraces microfluidic synthesis and fabrication of new materials with specific and sometimes, unique properties. Examples of such materials include silica colloids, microgel capsules, and polymer particles with specific morphologies (see Whitesides, G. M., Stone, H. A. Angew. Chemie, Intnl. Ed. 44, 724 (2005); (b) D. Dendukuri, K. Tsoi, T. A. Hatton and P. S. Doyle, Langmuir 21, 2113 (2005); S. A. Khan, A. Gunther, M. A. Schmidt, and K. F. Jensen, Langmuir 20, 8604 (2004); and (a) A. S. Utada, E. Lorenceau, D. R. Link, P. D. Kaplan, H. A. Stone, and D. A. Weitz, Science 2005, 308, 537 (2005); (b) Nie, Z.; Xu, S.; Seo, M.; Lewis P. C., Kumacheva, E. J. Amer. Chem. Soc. 127, 8058 (2005)).
Both groups of applications require multiple reactions and processes to be performed in parallel. For the second group, this requirement is vital: future progress in the development and production of new materials by microfluidic synthesis will be determined by the ability to scale up their production in multiple parallel continuous processes.
Currently, two groups of conventional technologies are used for the production of polymer colloids in the range from tens to hundreds of micrometers. In the first group, namely suspension polymerization methods, polymer particles are obtained by polymerizing monomer droplets that comprise oil-soluble initiators (see E. Vivaldo-Lima, P. E. Wood, A. E. Hamielec Ind. Eng. Chem. Res., 36, 939 (1997)). Droplets are produced by emulsifying liquid monomers in an aqueous phase in the presence of a stabilizing agent. Typically, particles obtained by suspension polymerization have a broad range of sizes, due to the insufficient control of the emulsification process and coalescence of droplets during their transportation to the reactor and in the course of polymerization. Generally, when a narrower distribution of sizes is required, the microbeads are fractionated. This time-consuming process leads to the loss of material. Although, membrane emulsification enhances droplet size distribution, coalescence of droplets in the course of polymerization still results in a broadened size distribution of the resulting particles (see G.-H. Ma, H. Sone, S. Omi. Macromolecules 37, 2954 (2004).
The second group, is referred to as the multi-step swelling method (the Ugelstadt method, see (a) J. Ugelstad, K. H. Kaggerud, F. K. Hansen, A. Berge. Macromol. Comm. 180, 737 (1979); (b) J. Ugelstad, L. Söderberg, A. Berge, I. Bergström, Nature 303, 95 (1983)). This time-consuming process involves the synthesis of small “precursor” particles that are used as seeds for the multi-stage synthesis of larger microbeads. When a monomer is added to the dispersion of precursor particles, it partitions and swells the seed particles. Subsequent polymerization of the swollen beads yields particles with an incremental increase in size. In order to obtain particles with dimensions exceeding 50 μm, the procedure is repeated several times.
At present, the microfluidic production of polymer particles includes (i) microfluidic emulsification of monomers or liquid pre-polymers and (ii) in-situ hardening of droplets by on-chip free-radical or condensation polymerization. In contrast with conventional suspension polymerization, microfluidic synthesis in an individual microreactor produces particles with an extremely narrow size distribution, due to the specific mechanisms of microfluidic emulsification and continuous “on-chip” polymerization of the droplets that prevents droplet coalescence. In addition, microfluidic polymerization yields particles with a range of precisely controlled shapes and morphologies.
A single microfluidic droplet generator typically has a productivity in the range from 103 to 106 droplets/hour, which corresponds to the productivity in particle synthesis. In order to favorably compete with conventional polymerization strategies, the generation of droplets has to be scaled up by producing them in multiple parallel droplet generators. Furthermore, to preserve the advantages of microfluidic emulsification, the droplets obtained in parallel devices should maintain their narrow size distribution.
Scalable polymerization of polymer particles has been reported in sixteen individual microfluidic reactors with eight inlets for the monomer droplet phase and sixteen inlets for the continuous aqueous phase, that were placed in a concentric manner on a single microfluidic chip (T. Nisisako, T. Torii, T. Takahashi, Y. Takizawa, Adv. Mater. 18, 1152-1156 (2006)). Although detailed analysis of the variation in sizes of particles produced in multiple microchannels has not been reported, the authors claimed that polymerization of monomer droplets yielded up to 20 g h−1 of particles with polydispersity 3%. This device requires multiple (at least 16) syringe pumps to supply two liquids to each microfluidic such that such a system is quite expensive.
The challenge in the scaled up microfluidic synthesis of polymer particles in multichannel microfluidic reactors is to preserve the advantages of synthesis in a single-channel microfluidic reactor: a narrow size distribution and controllable structure of particles, arising from the highly controlled microfluidic emulsification and the high conversion of monomers, without a significant increase in the microreactor dimensions and the use of multiple pumps supplying liquids to each microreactor. The last two requirements can be satisfied requirements in a combined microfluidic reactor with two inlets for the droplet and continuous phases.
Multichannel microfluidic devices have been used for DNA separation, parallel PCR assays, detection of enzymatically-generated fluorescence and linear temperature gradients, capillary electrophoresis for immunoassays, and chiral separation (see Zheng, B.; Ismagilov, R. F. Angew. Chem., Int. Ed. 2005, 44, 2520; J. S. Marcus, W. F. Anderson, and S. R. Quake, Anal. Chem., 2006, 78, 956, A. T. Woolley, G. Sensabaugh, and R. A. Mathies, Anal. Chem., 1997, 69, 2181; Y. Shi, P. C. Simpson, J. R. Scherer, D. Wexler, C. Skibola, M. T. Smith, and R. A. Mathies, Anal. Chem. 1999, 71, 5354; H. Mao, T. Yang, and P. S. Cremer, J. Am. Chem. Soc., 2002, 124, 4432; M. Herrmann, T. Veres, and M. Tabrizian, Lab Chip, 2006, 6, 555; Y. Gao, Z. Shen, H. Wang, Z. Dai, and B. Lin, Electrophoresis, 2005, 26, 4774; S. B. Cheng, C. Skinner, J. Taylor, S. Attiya, W. E. Lee, G. Picelli, and D. J. Harrison, Anal. Chem., 2001, 73, 1472).
In these reports, emulsification in parallel combined microfluidic channels was not used. Typically, implementation of multiple droplet generators on a planar microfluidic chip entails experimental challenges such as an easy supply of liquids, realization of identical geometries of individual droplet generators, and controlled and reproducible flow rates of liquids in microchannels. Recently, several approaches to the production of droplets or plugs with identical or alternating composition were proposed that employed break up of liquid plugs at T-junctions, geometrically mediated breakup of droplets and flow-focusing devices placed in a series (see V. Barbier, H. Willaime, and P. Tabeling, Phys. Rev. E, 2006, 74, 046306; 26. B. Zheng, J. D. Tice and R. F. Ismagilov, Anal. Chem., 2004, 76, 4977; B. Zheng, L. S. Roach and R. F. Ismagilov, J. Am. Chem. Soc., 2003, 125, 11170; D. N. Adamson, D. M, John, X. J. Zhang, B. Zheng, and R. F. Ismagilov, Lab Chip, 2006, 6, 1178; D. R. Link, S. L. Anna, D. A. Weitz, and H. A. Stone, Phys. Rev. Lett., 2004, 92, 054503; P. Garstecki, M. J. Fuerstman, H. A. Stone, and G. M. Whitesides, Lab Chip, 2006, 6, 437; P. Garstecki, M. J. Fuerstman and G. M. Whitesides, Nat. Phys., 2005, 1, 168; H. Song, J. D. Tice and R. F. Ismagilov, Angew. Chem. Int. Ed., 2003, 42, 768).
To date, a single report exists on the synchronization of formation of droplets in the device comprising two parallel combined microfluidic droplet generators with T-junctions with two inlets (see V. Barbier, H. Willaime, P. Tabeling. Phys. Rev. E 74, 046306 (2006)). The authors showed the broadening in droplet size distribution due to the parametric coupling between the individual devices, and, found that a narrow polydispersity of the droplets was achieved when emulsification in the two microchannels was synchronized.
In comparison with formation of droplets at T-junctions, the flow-focusing mechanism used in the present invention discussed hereinafter has higher emulsification efficiency and allows better control over droplet size and size distribution. It is also not obvious whether the results obtained in two droplet generators can be projected to the muff/channel device with combined microchannels; with an increasing number of microchannels, the requirement for synchronization between them may become problematic.
In addition to the scaled up synthesis of polymer particles, emulsification in parallel droplet generators is also important in fast-throughput screening of the effect of a particular event or variable in a chemical or physical process, e.g., in optimization of conditions of chemical reactions or in studies of the effect of the surface energy and geometry of the microfluidic device on the formation of droplets.